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Transcription factor 7 like 2 (TCF7L-2) polymorphism has been associated with adipocyte metabolism and insulin resistance. Genetic investigations of non-alcoholic fatty liver disease (NAFLD) with obesity, type 2 diabetes mellitus (T2DM) and atherosclerosis are unknown. This study was designed to investigate the association of rs7903146 (C/T) polymorphism of TCF7L-2 gene with non-alcoholic fatty liver disease (NAFLD) in Asian Indians. In this case-control study 162 non-diabetic subjects with NAFLD and 173 body mass index (BMI)-matched controls without NAFLD were recruited. Abdominal ultrasound, clinical and biochemical investigations, fasting insulin levels and value of homeostasis model assessment of insulin resistance (HOMA-IR) was measured. Single nucleotide polymorphism rs7903146 (C/T) was genotyped by polymerase chain reaction – restriction fragment length polymorphisms. The distribution of rs7903146 (C/T) alleles , the dominant model (CT + TT) and higher frequency (31%) of C/T genotype were significantly associated with NAFLD. C/T genotype of TCF7L2 gene was associated with significantly higher levels of BMI (p = 0.02), abdominal obesity (p < 0.05), fasting blood glucose (p = 0.05), hepatic transaminases (p < 0.05) and markers of insulin resistance (p < 0.05) in subjects with NAFLD. Using a multivariate analysis after adjusting for age and sex, TCF7L2 polymorphism was independently associated with presence of NAFLD [(OR: 3.234 (95% CI: 1.219 - 4.160, p = 0.002)]. TCF7L2 (C/T) gene was Independently associated with NAFLD in Asian Indians. • In this study, 162 NAFLD and 173 without NAFLD were single nucleotide polymorphism rs7903146 (C/T) was genotyped. • Mean Values of BMI, abdominal obesity, lipids and hepatic levels were significantly increased in NAFLD subjects. • Higher frequencies of C/T and T/T genotypes of TCF7L2 gene were obtained in NAFLD subjects as compared to controls. • In multivariate analysis, TCF7L2 polymorphism was independently associated with presence of NAFLD. [ABSTRACT FROM AUTHOR]